Recognizing that the complexity of cancer biology makes it virtually impossible for any single therapy to be optimally effective, the overall hypothesis of this research is that, two or more therapies that are mechanistically independent and directed at non-overlapping molecular targets and pathways will provide the most effective treatments. In particular, the dismal statistics for Pancreatic Cancer (PanCa) and its tenacious resistance to current therapies demand innovative approaches with sound mechanistic bases. The goal of this Project is to develop mechanism-based Photodynamic Therapy (PDT) combination regimens to synergistically enhance efficiency of PDT in preclinical models of PanCa where PDT alone has already shown promise. The strategy is to combine PDT with a biologic therapy that is specific to the particular molecular response elicited by PDT in an approach we term Combination Photodynamic Biologic Therapy (CPBT). PDT is an effective treatment for cancer, which kills most cells in solid tumors, and although molecular responses instigated by surviving cells could mitigate overall treatment outcome, these same responses also provide an opportunity in new molecular targets that could greatly enhance specificity and efficiency of treatment outcome. The goals of the study will be realized in 5 specific aims. Aim 1 will examine molecular responses to sub-lethal PDT and test CPBT targeted to these responses in in vitro organotypic cultures. Aim 2-5 will utilize an orthotopic model of PanCa where Aim 2 will optimize PDT parameters in vivo and along with information on the success of CPBT in Aim 1, will guide PDT-based combination treatments in vivo, in Aim 3. Since Gem is standard chemotherapy for PanCa, successful combination treatments in Aim 3 will be further examined in combination with Gem in Aim 4. Finally, the two most successful treatments from Aim 4 will be extended to a long-term survival study in Aim 5. Cores B and C will be used throughout; e.g. on-line measurement of molecular responses, PDT dosimetry, pathology and statistical considerations. The promise of PDT in clinical studies and in several preclinical models for PanCa, our significant preliminary findings and collaborations within the program provide the impetus for the proposed investigations. Potential benefits to public health: the studies in Project 3will lead to newtreatment options for PanCa, a disease with a very poor prognosis with current treatments placing a heavy burden on society in terms of cost and suffering.